Blood platelets are required for the maintenance of normal hemostasis. Platelets initiate blood clot formation and release growth factors that speed the process of wound healing as well as potentially serving other functions. Platelets are the terminal differentiation product of megakaryocytes, which in turn originate from pluripotent stem cells of the bone marrow. The maturation and differentiation processes that begin with pluripotent stem cells and end with blood platelets are complex and incompletely understood. However, it is thought that humoral factors influence different cellular steps in megakaryocyte development.
A number of diseases or conditions result frown inappropriate levels or inadequate function of blood platelets. For example,"thrombocytopenias" are the result of an abnormally small number of platelets in the circulating blood. Thombocytopenia can be due to antibody mediated platelet destruction (Karpatkin, S., Sem in Hematol., 22:260-288 (1985)), massive blood transfusions, cardio-pulmonary by-pass or bone marrow failure from malignant infiltration, aplastic anemia or chemotherapy (Heyman, M. R., and C. A. Schiffer, Sem. Onc., 17:198 (1990)). "Thrombocythemic" disorders, on the other hand, are the result of a high platelet count. Finally, "thrombocytopathic" blood disorders are characterized by abnormally low or high platelet function, although platelet counts may be normal.
Platelet disorders are clinically managed primarily by whole blood or platelet transfusions. However, blood and platelet supplies can become limited. Also, storage of platelet and whole blood preparations can be problematic. For example, it has been found that normal human platelets have a "shelf-life" of approximately 5 days. In addition, transfusions can transmit infection and are costly. Further patients are often refractory to subsequent transfusions. In view of the problems associated with available therapies, many researchers have been working to identify, humoral factors involved with platelet generation, which would be clinically useful. Although a number of putative megakaryocyte growth promoting factors have been identified to date (e.g., thrombopoietin (Hill, R. J. et. al., Exp. Hematol. 20:354 (1992)); thrombopoietic stimulatory factor (McDonald, T. P. Exp, Hematol. 16:201 ( 1988)); megakaryocyte stimulatory factor (Tayrien, G. et. al., J. Biol,.Chem,. 262:3262 (1987), and Greenberg, S. M. et. al., J. Biol. Chem. 262:3269 (1987)) Il-1 (Monroy, RL et. al., Exp Hematol. 9:629 (1991)); Il-6 (Williams, N. Exp. Hematol. 19:714 (1991)); Il-11 (Goldman, SJ et. al., Blood 80:91a (1992)); and erythropoietin (Berridge, MV et. al., Blood 72:970 (1988)), none has been shown to possess all of the physiological properties expected of a humoral stimulator of platelet production (i.e., low basal levels; circulating levels which vary reciprocally and proportionally to changes in platelet mass; lag period before the level of the circulating factor changes in response to alterations in the platelet mass; and suppression of the levels of the factor following platelet transfusion).
Isolation of a true "megakaryocyte growth promoting factor" would be useful for treating blood platelet disorders.